Molecular Imaging to Study Radio-Protection by Cerium Oxide Nanoparticles

 描述(申请人提供)：与化疗和手术一样，放射治疗(RT)是癌症的主要治疗选择。它是全球5000多万癌症幸存者治疗计划的一部分。即使在适形图像引导治疗方面取得了进展，RT仍然受到正常组织损伤的限制。RT的短期和长期副作用都与RT有关，包括贫血、胃肠道不适、皮肤刺激、组织纤维化，甚至继发性癌症。这些都影响了许多患者在RT期间的生活质量。RT通过产生自由基来杀死细胞，从而压倒细胞清除自由基的保护机制，导致DNA损伤。作为一种预防措施，抗氧化剂已经被发现可以补充细胞清除自由基的能力，并减少RT的副作用。这些药物都有自己的副作用，它们是否也能保护肿瘤组织尚不清楚，这导致了对它们使用的争议。氧化铈纳米颗粒(CONPs)是由稀土元素Ce的氧化物制成的，它可能是一种新的潜在的治疗方法，用于保护正常组织免受RT的伤害。碳纳米粒子已被用作工业催化剂，以其独特的氧化还原化学而闻名，最近因其生物医学应用而被研究。CONPs已经证明可以保护细胞免受炎症、氧化和辐射损伤所产生的自由基的伤害，而且与剂量相关的毒性最小。已经证明，CONPs不能保护癌细胞免受辐射损伤，尽管这种辐射保护丧失的机制尚不清楚。这个项目试图通过试图发现肿瘤微环境(TME)，特别是低pH和低氧对CONPs辐射防护特性的影响，来显著增加对这些机制的理解。PH和低氧是本研究的重点，因为CONPs在较低的PHS时失去氧化还原特性，而TME的低氧条件对自由基产生和肿瘤放射抗性至关重要，也可能影响CONPs在肿瘤组织中的反应。CONPs的作用已经在体内进行了研究，但在临床模拟治疗条件下的机制研究还很缺乏。这项提议将利用多种方式 分子成像和适形成像引导RT以更好地理解CONPs在自发诱导的结肠癌小鼠模型中的辐射防护的潜在机制。分子成像将包括放射性标记的CONPs(RCONPs)的SPECT/PET-CT成像，以测量摄取和药代动力学，而磁共振成像和断层光声成像(TPA)将用于确定体内的pH和氧气梯度。[18F]FDG PET成像将用于监测肿瘤生长和肿瘤/正常组织对放射治疗的反应。将正常/肿瘤组织对rCONPs摄取和体内pH/O2条件的反应与体外交叉验证进行比较，将揭示它们是如何相互关联的。这样做的方法 该项目的结果与临床上可用的结果相当，来自这些研究的信息可能有助于加快CONP转化为RT临床试验。

 DESCRIPTION (provided by applicant): Along with chemotherapy and surgery, radiation therapy (RT) is a leading treatment option for cancer. It is an element in the treatment plan of over 50 million cancer survivors worldwide. Even with advances in conformal image guided therapies, RT is still limited by damage to normal tissues. Both short and long term side effects have been associated with RT, including anemia, gastrointestinal distress, skin irritation, tissue fibrosis, and even secondary cancer. These compromise the quality of life for many patients during RT. RT kills cells through free radical generation that overwhelms cells' radical scavenging protective mechanisms, leading to DNA damage. As a preventive measure, antioxidant drugs have been discovered that can supplement cells' radical scavenging and reduce RT side effects. These drugs have their own side effects and whether they also protect tumor tissue is unclear, leading to controversy over their use. Cerium oxide nanoparticles (CONPs), made from an oxide of the rare-earth element cerium, may be a novel potential therapeutic for their application as protectors of normal tissue from RT. CONPs have been used as industrial catalysts, are well known for their unique redox chemistry, and have recently been investigated for their biomedical applications. CONPs have demonstrated protection of cells from free radicals produced by inflammatory, oxidative, and radiation damage, with minimal dose related toxicity. It has been shown that CONPs do not protect cancer cells from radiation damage, though the mechanisms of this loss of radio-protection are poorly understood. This project attempts to significantly increase understanding of these mechanisms by attempting to discover the effects of the tumor microenvironment (TME), specifically low pH and hypoxia, on CONPs' radio-protective properties. pH and hypoxia are the focus of this study because CONPs lose their redox properties at lower pHs, and the hypoxic conditions of the TME are critical to radical production and tumor radio-resistance and may also affect how CONPs react in tumor tissue. The effects of CONPs have been studied in vivo, but there is a lack of mechanistic studies under clinically simulating treatment conditions. This proposal will utilize multi-modality molecular imaging and conformal image guided RT to better understand the underlying mechanisms of CONPs' radio- protection in a spontaneously induced colon cancer mouse model. Molecular imaging will consist of SPECT- /PET-CT imaging of radiolabeled CONPs' (rCONPs) to measure uptake and pharmacokinetics, while MRI and tomographic photoacoustic imaging (TPA) will be used to determine in vivo pH and oxygen gradients. [18F]FDG PET imaging will be used to monitor tumor growth and tumor/normal tissue response to RT. Comparing the normal/tumor tissue response to the rCONPs' uptake and the pH/O2 conditions in vivo, with in vitro cross validation, will reveal how they are interrelated. The methods of this project are comparable to those available in the clinic and information from these studies may help accelerate CONP translation into RT clinical trials.